WO2013191128A1

WO2013191128A1 - Skin patch

Info

Publication number: WO2013191128A1
Application number: PCT/JP2013/066574
Authority: WO
Inventors: 瑛介畠中; 高田　恭憲; 寺原　孝明; 肥後　成人
Original assignee: 久光製薬株式会社
Priority date: 2012-06-20
Filing date: 2013-06-17
Publication date: 2013-12-27
Also published as: EP2865378B1; PT2865378T; US9308187B2; JP5758050B2; ES2656949T3; JPWO2013191128A1; KR102009546B1; EP2865378A1; CN104379139A; TWI592169B; EP2865378A4; CN104379139B; US20150202171A1; KR20150023758A; HUE037454T2; TW201406411A

Abstract

A skin patch provided with a support layer and an adhesive layer, wherein the adhesive layer contains diclofenac sodium, dimethyl sulfoxide, and citric acid; the mass ratio of the diclofenac sodium and the citric acid (the mass of the diclofenac sodium:the mass of the citric acid) being 1:0.15 to 1:0.45, and the mass ratio of the diclofenac sodium and the dimethyl sulfoxide (the mass of the diclofenac sodium:the mass of the dimethyl sulfoxide) being 1:0.75 to 1:3.

Description

Patch

The present invention relates to a patch.

Diclofenac is an excellent non-steroidal anti-inflammatory analgesic, but there is a problem that when it is administered orally, it may show side effects such as gastrointestinal disorders. For this reason, various topical preparations containing diclofenac as an active ingredient have been developed. In Japan, a patch containing diclofenac sodium is marketed as a drug for local analgesia.

However, these patches are characterized by good skin permeability of diclofenac, but their indication is limited to local analgesic anti-inflammatory. Unlike conventional topical preparations on the market, diclofenac is stably contained at a high concentration, has superior drug release ability and skin permeability, and the blood concentration of diclofenac in the administration subject If it can be as high as administration with a suppository, it can be effective for systemic symptoms (anti-inflammatory analgesia, antipyretic, etc.), so such new diclofenac and / or its pharmacologically acceptable It has been desired to develop a patch containing such a salt.

In addition, diclofenac contained in patches currently on the market or under development is improved in stability and physical properties (strength, elasticity, durability, adhesiveness, etc.) of the adhesive layer of the patch. In many cases, it is used in the form of a pharmaceutically acceptable salt, particularly a sodium salt, from the viewpoints of suppression of skin irritation and reduction of skin irritation. However, although diclofenac sodium is hardly soluble in ether, it is relatively easy to dissolve in water, and its percutaneous absorbability is not sufficient, so various ideas have been made.

For example, Japanese Patent Application Laid-Open No. Sho 61-280426 (Patent Document 1) discloses that diclofenac sodium in a patch is prepared by containing diclofenac sodium in combination with an organic acid in the pressure-sensitive adhesive material layer of an anti-inflammatory analgesic patch. It improves the solubility and skin permeability. Japanese Patent Application Laid-Open No. 62-181226 (Patent Document 2) discloses that diclofenac sodium is combined with an organic acid and further glycols and contained in the base of an anti-inflammatory analgesic patch. It has been described to improve the solubility and skin permeability of diclofenac sodium. Furthermore, JP-A-2002-338462 (Patent Document 3) contains diclofenac sodium, an organic acid, pyrrolidone or a derivative thereof, and a polyhydric alcohol fatty acid ester in combination in an adhesive paste base. Describes that diclofenac sodium in the base is stably dissolved and improves the release from the plaster and the transdermal absorbability.

Japanese Patent Laid-Open No. 61-280426 Japanese Patent Laid-Open No. 62-181226 JP 2002-338462 A

As described above, the skin permeability of diclofenac sodium in the patch is improved by containing citric acid or the like as an organic acid. However, as a result of the study by the present inventors, as shown in the examples described later, when diclofenac sodium and citric acid were simply blended, in the adhesive layer of the patch, diclofenac or diclofenac sodium crystallized over time. It became clear that would occur. Therefore, in the anti-inflammatory analgesic patches described in Patent Documents 1 to 3, diclofenac or diclofenac sodium crystallizes with time, so diclofenac sodium is stably contained in the adhesive layer at a high concentration. However, these anti-inflammatory analgesic patches are not sufficient, and as a result, the effectiveness against systemic symptoms (anti-inflammatory analgesia, antipyretic, etc.) could not be expected by transdermal administration of diclofenac.

The present invention has been made in view of the above-described problems of the prior art, and an object of the present invention is to provide a patch that suppresses crystal precipitation of diclofenac and diclofenac sodium and has excellent skin permeability of diclofenac. .

As a result of intensive studies to achieve the above object, the present inventors have found that, in various solubilizers, dimethyl sulfoxide, N-methylpyrrolidone, polyethylene glycol, and dipropylene glycol are excellent in solubility of diclofenac sodium and diclofenac. It became clear that. In particular, it was also found that dimethyl sulfoxide exhibits excellent skin permeability even when diclofenac sodium with low skin permeability is used when a styrene-isoprene-styrene block copolymer is used in the adhesive layer of the patch.

However, when dimethyl sulfoxide is blended in the pressure-sensitive adhesive layer, the solubility of diclofenac sodium in the initial stage of production is good, but crystals form over time, and like citrate, the dimethyl sulfoxide alone has diclofenac sodium. It was unsuitable for use in patches as a solubilizer.

However, as a result of further earnest studies to achieve the above object, the present inventors have used dimethyl sulfoxide as a solubilizer when diclofenac sodium is contained in the adhesive layer of the patch, and further uses citric acid. It has been found that the crystal precipitation of diclofenac and diclofenac sodium can be suppressed by containing at a predetermined mass ratio with respect to diclofenac sodium. In addition, a patch comprising an adhesive layer containing diclofenac sodium, dimethyl sulfoxide and citric acid at a predetermined mass ratio is superior to a patch containing conventional citric acid and diclofenac sodium. It was also revealed that it has skin permeability. Furthermore, the patch using dimethyl sulfoxide as a solubilizer has strong irritation to the skin, but it has also been found that this irritation can be reduced by using it together with citric acid, and the present invention has been completed.

That is, the patch of the present invention is a patch comprising a support layer and an adhesive layer, wherein the adhesive layer contains diclofenac sodium, dimethyl sulfoxide and citric acid, and the diclofenac sodium The mass ratio of citric acid (mass of diclofenac sodium: mass of citric acid) is 1: 0.15 to 1: 0.45, and the mass ratio of diclofenac sodium and dimethyl sulfoxide (mass of diclofenac sodium) : Mass of dimethyl sulfoxide) is 1: 0.75 to 1: 3.

In the pressure-sensitive adhesive layer according to the present invention, the mass ratio of diclofenac sodium and dimethyl sulfoxide is preferably 1: 0.75 to 1: 2. Furthermore, the pressure-sensitive adhesive layer preferably further contains oleic acid.

According to the present invention, it is possible to provide a patch in which the crystal precipitation of diclofenac and diclofenac sodium is suppressed, there is little irritation to the skin, and the skin permeability of diclofenac is excellent.

It is a graph which shows the solubility of diclofenac with respect to various solvents. It is a graph which shows the solubility of diclofenac sodium with respect to various solvents. It is a graph which shows the time-dependent change of the cumulative skin permeation amount of diclofenac in the skin of a hairless mouse to which a patch containing diclofenac sodium is applied. It is a graph which shows the time-dependent change of the cumulative skin permeation amount of diclofenac in human skin to which a patch containing diclofenac sodium is applied. Change in blood concentration with time when one patch of the present invention (Example 2) was applied to the skin, and diclofenac sodium-containing oral preparation (Voltaren (registered trademark) tablet or Voltaren (registered trademark) SR capsule) was orally administered. It is a graph which shows the result estimated using simulation software about the time-dependent change of the blood concentration at the time of administration. Changes in blood concentration over time when two patches of the present invention (Example 2) were applied to the skin, and oral diclofenac sodium-containing oral preparations (Voltaren (registered trademark) tablets or Voltaren (registered trademark) SR capsules) It is a graph which shows the result estimated using simulation software about the time-dependent change of the blood concentration at the time of administration. Changes in blood concentration over time when 3 sheets of the patch of the present invention (Example 2) were applied to the skin, and diclofenac sodium-containing oral preparations (Voltaren (registered trademark) tablets or Voltaren (registered trademark) SR capsules) were orally administered. It is a graph which shows the result estimated using simulation software about the time-dependent change of the blood concentration at the time of administration. 5 is a graph showing the results of water release analysis of diclofenac sodium-containing patches (Examples 5 to 9, Comparative Examples 10 and 11).

Hereinafter, the present invention will be described in detail on the basis of preferred embodiments thereof.

The patch of the present invention comprises a support layer and an adhesive layer formed on the surface of the support layer (usually on one surface), and diclofenac sodium, dimethyl sulfoxide and citric acid are added to the adhesive layer. It is contained in the agent layer.

First, the pressure-sensitive adhesive layer according to the present invention will be described. The pressure-sensitive adhesive layer used in the present invention is usually formed on one side of the support layer, and can be applied to the skin or the like, and should be percutaneously absorbed with a pressure-sensitive adhesive. It is a layer containing diclofenac sodium.

Diclofenac sodium according to the present invention is a non-steroidal analgesic and anti-inflammatory drug, and is also a compound called sodium 2-[(2,6-dichlorophenyl) amino] phenylacetate.

In the patch of the present invention, the content of such diclofenac sodium can be appropriately adjusted depending on the purpose of treatment, but is generally 1 to 20% by mass relative to the total mass of the adhesive layer. From the standpoint that therapeutic effects are easily exhibited and suitable adhesive properties are easily obtained, the content is preferably 2 to 10% by mass.

The patch of the present invention contains dimethyl sulfoxide and citric acid in the pressure-sensitive adhesive layer, thereby suppressing crystal precipitation of diclofenac and diclofenac sodium and increasing the concentration of diclofenac sodium (relative to the total mass of the pressure-sensitive adhesive layer). 3% by mass or more). Furthermore, since the drug release property (water release property) from the pressure-sensitive adhesive layer is high, the patch of the present invention can exhibit excellent skin permeability of diclofenac. Moreover, the patch of this invention can reduce the irritation | stimulation with respect to skin by containing a dimethylsulfoxide and a citric acid in the said adhesive layer.

The content of the dimethyl sulfoxide is preferably 1 to 15% by mass and more preferably 3 to 10% by mass with respect to the total mass of the pressure-sensitive adhesive layer. When the content of dimethyl sulfoxide is less than the lower limit, diclofenac or diclofenac sodium crystals tend to precipitate. On the other hand, when the content exceeds the upper limit, the adhesive strength or cohesive strength of the adhesive is reduced. Tend to.

The citric acid according to the present invention may be citric anhydride or citric acid hydrate, and citrate (for example, sodium citrate, potassium citrate, magnesium citrate, citric acid) Calcium) may be used. The citric acid content is preferably 0.15 to 9% by mass and more preferably 0.25 to 5% by mass with respect to the total mass of the pressure-sensitive adhesive layer. When the citric acid content is less than the lower limit, diclofenac or diclofenac sodium crystals tend to precipitate, and the irritation to the skin tends to increase, whereas, when the upper limit is exceeded, Diclofenac or diclofenac sodium crystals tend to precipitate, and the content of diclofenac sodium over time tends to decrease.

Further, in the pressure-sensitive adhesive layer according to the present invention, the mass ratio of diclofenac sodium and citric acid (diclofenac sodium mass: citric acid mass) needs to be 1: 0.15 to 1: 0.45. It is preferably 1: 0.15 to 1: 0.30 (molar ratio of the diclofenac sodium to the citric acid is required to be 1: 0.25 to 1: 0.75. ). When the ratio of the mass of citric acid to the mass of diclofenac sodium is less than the lower limit, diclofenac or diclofenac sodium crystals are precipitated, and there is a tendency that it is difficult to obtain therapeutically effective diclofenac skin permeability. On the other hand, even if the upper limit is exceeded, diclofenac or diclofenac sodium crystals tend to precipitate.

In the pressure-sensitive adhesive layer according to the present invention, the mass ratio of diclofenac sodium to dimethyl sulfoxide (the mass of diclofenac sodium: the mass of dimethyl sulfoxide) needs to be 1: 0.75 to 1: 3. 1: 0.75 to 1: 2. When the ratio of the mass of the dimethyl sulfoxide to the mass of the diclofenac sodium is less than the lower limit, the drug release property (water release property) of the pressure-sensitive adhesive layer is reduced, and diclofenac or diclofenac sodium crystals are likely to precipitate. On the other hand, if the upper limit is exceeded, sufficient adhesive strength to the skin or the like tends to be difficult to obtain.

Furthermore, in the pressure-sensitive adhesive layer according to the present invention, the total content of the citric acid and the dimethyl sulfoxide can be appropriately adjusted according to the amount of the diclofenac sodium, but the total mass of the pressure-sensitive adhesive layer The content is preferably 0.5 to 20% by mass, and more preferably 1 to 15% by mass. When the total content is less than the lower limit, the skin permeability of diclofenac tends to decrease, and crystals of diclofenac or diclofenac sodium tend to precipitate. The adhesive strength or cohesive strength of the agent tends to decrease.

The pressure-sensitive adhesive layer according to the present invention preferably further contains oleic acid from the viewpoint of further improving the skin permeability of diclofenac. In addition, the content of oleic acid or the like is preferably 1 to 10% by mass with respect to the total mass of the pressure-sensitive adhesive layer. When the total content is less than the lower limit, the skin permeability of diclofenac tends to decrease and the therapeutic effect tends to decrease, whereas when the upper limit is exceeded, the adhesive strength of the adhesive or The cohesive force tends to decrease.

Further, the pressure-sensitive adhesive that the pressure-sensitive adhesive layer according to the present invention contains is not particularly limited, and examples thereof include rubber-based pressure-sensitive adhesives, acrylic pressure-sensitive adhesives, polyurethane-based pressure-sensitive adhesives, silicon-based pressure-sensitive adhesives, The hydrogel which consists of aqueous polymer, or a mixture thereof is mentioned. Furthermore, if necessary, the pressure-sensitive adhesive layer may contain a tackifier, a plasticizer, other additives and the like.

Such a rubber-based adhesive is a non-aqueous or anhydrous adhesive composition mainly composed of natural rubber and / or synthetic rubber. Examples of such synthetic rubber include polyisoprene, polyisobutylene, polybutadiene, styrene-butadiene-styrene block copolymer, styrene-isoprene-styrene block copolymer, styrene-butadiene rubber, and styrene-isoprene rubber. These can be used alone or in combination. Among these, styrene-isoprene-styrene block copolymer and / or polyisobutylene are preferable from the viewpoints of further enhancing the skin permeability of diclofenac and also increasing the cohesive strength of the patch of the present invention.

The total content of natural rubber and / or synthetic rubber is preferably 10 to 40% by mass, more preferably 15 to 35% by mass with respect to the total mass of the pressure-sensitive adhesive layer. When the total content is less than the lower limit, the cohesive force of the pressure-sensitive adhesive tends to decrease and the glue residue tends to increase. On the other hand, when the total content exceeds the upper limit, the cohesive force of the pressure-sensitive adhesive increases. The adhesive strength tends to decrease, and the patch productivity tends to decrease.

Examples of the acrylic pressure-sensitive adhesive include (meth) acrylic acid, (meth) acrylic acid-2-ethylhexyl, methyl (meth) acrylate, butyl (meth) acrylate, hydroxyethyl (meth) acrylate, and the like. An adhesive obtained by polymerizing or copolymerizing at least one of the (meth) acrylic monomers. Furthermore, as such a polyurethane adhesive, for example, an aliphatic polyurethane adhesive and an aromatic polyurethane adhesive can be used, and as such a silicone adhesive, for example, polydimethylsiloxane, polymethylvinylsiloxane. A material mainly composed of silicon rubber such as polymethylphenylsiloxane can be used. Further, as the hydrogel composed of such an aqueous polymer, for example, a gel mainly composed of gelatin, carrageenan, hydroxyethyl cellulose or the like can be used.

Examples of the tackifier include rosin ester, hydrogenated rosin ester, maleated rosin, alicyclic saturated hydrocarbon resin, and terpene resin. Among these, diclofenac has high skin permeability, and can be applied to the skin. From the viewpoints of low irritation and easy to obtain suitable adhesive properties, alicyclic saturated hydrocarbon resins, hydrogenated rosin esters and terpene resins are preferred. Further, as the tackifier, specifically, ester gum A, AA-G, H or HP (trade name, manufactured by Arakawa Chemical Industries, Ltd.), Harrier Star L, S or P (trade name, Arakawa Chemical Industries) Pine crystal KE-100 (trade name, manufactured by Arakawa Chemical Co., Ltd.), KE-311 (trade name, manufactured by Arakawa Chemical Co., Ltd.), Hercolin D (trade name, manufactured by Rika Hercules Co., Ltd.), Foral 85 or 105 (trade name, manufactured by Rika Hercules Co., Ltd.), Stevelite Ester 7 or 10 (trade name, manufactured by Rika Hercules Co., Ltd.) Pentaline 4820 or 4740 (trade name, manufactured by Rika Hercules Co., Ltd.), Alcon P-85 Or, P-100 (trade name, manufactured by Arakawa Chemical Co., Ltd.), YS resin (trade name, manufactured by Yasuhara Chemical Co., Ltd.).Moreover, as this tackifier, you may use individually by 1 type, or may be used in combination of 2 or more type.

Furthermore, the total content of the tackifier is preferably 5 to 60% by mass, and more preferably 10 to 50% by mass with respect to the total mass of the adhesive layer. When the total content is less than the lower limit, the adhesive strength and long-term skin adhesion tend to be reduced. On the other hand, when the upper limit is exceeded, the transdermal absorbability and shape retention of diclofenac. Etc., and pain at the time of peeling of the patch, skin irritation, stickiness, etc. tend to increase.

Examples of the plasticizer include petroleum oils (for example, paraffinic process oil, naphthenic process oil or aromatic process oil), squalane, squalene, vegetable oils (for example, almond oil, olive oil, camellia oil, castor oil). , Tall oil, peanut oil), dibasic acid ester (for example, dibutyl phthalate, dioctyl phthalate), liquid rubber (for example, liquid polybutene, liquid isoprene rubber, etc.), and using one of these alone May also be used in combination of two or more. The plasticizer is preferably liquid paraffin or liquid polybutene from the viewpoint that the adhesion to the skin tends to be further improved.

Furthermore, the total content of the plasticizer is preferably 7 to 70% by mass, and more preferably 10 to 60% by mass with respect to the total mass of the pressure-sensitive adhesive layer. When the total content is less than the lower limit, the adhesive strength, the transdermal absorbability of diclofenac and the dispersibility of diclofenac sodium tend to decrease, while when the upper limit is exceeded, the cohesive strength, the shape retention property Tend to decrease, and the pain and stickiness at the time of peeling of the patch tend to increase.

In the pressure-sensitive adhesive layer according to the present invention, an antioxidant (for example, ascorbic acid, propyl gallate, butylhydroxyanisole, dibutylhydroxytoluene (BHT), nordihydroguaiaretic acid, tocopherol, Tocopherol acetate), ultraviolet absorbers (eg, paraaminobenzoic acid, paraaminobenzoic acid ester, amyl paradimethylaminobenzoic acid, salicylic acid ester, methyl anthranilate, umbelliferone, esculin, benzyl cinnamate, sinoxate, guaiazulene, urocanic acid, 2- (2-hydroxy-5-methylphenyl) benzotriazole, 4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone, octapentone, dioxybenzone, dihydroxydimethoxy Nzophenone, sulinpenzone, benzolercinol, octyldimethylparaaminobenzoate, ethylhexylparamethoxycynamate), antibacterial agent (eg, paraoxybenzoate, benzoic acid, benzoate, sorbic acid, sorbate, dehydroacetate, 4- Isopropyl-3-methylphenol, 2-isopropyl-5-methylphenol, hinokitiol, cresol, 2,4,4-trichloro-2'-hydroxydiphenyl ether, 3,4,4'-trichlorocarbanide chlorobutanol, etc.), packing Agents (eg, aluminum hydroxide, hydrous aluminum silicate, kaolin, titanium oxide, talc, zinc oxide, hydrous silica, magnesium carbonate, calcium hydrogen phosphate, magnesium silicate, diatomaceous earth, anhydrous silicic acid, ben Knight, sodium stearate, calcium stearate, potassium stearate, magnesium stearate, zinc stearate), cooling agents, may be blended perfumes.

The pressure-sensitive adhesive layer according to the present invention is a layer containing the above-described components, and may be a single layer composed of one kind of composition, or may be a multilayer composed of a plurality of layers having different compositions. Good. The thickness of the pressure-sensitive adhesive layer is usually 10 to 500 μm, and is preferably 30 to 300 μm from the viewpoint that suitable adhesion to the skin and good production suitability can be easily obtained.

Next, the support layer according to the present invention will be described. The support layer used in the present invention holds the above-mentioned pressure-sensitive adhesive layer. Polyethylene, polypropylene, polybutadiene, ethylene-vinyl acetate copolymer, vinyl acetate-vinyl chloride copolymer, polyvinyl chloride, polyamide, polyester, nylon, cellulose derivatives, synthetic resin films, sheets, sheet-like porous materials such as polyurethane A body, a sheet-like foam, a woven fabric, a knitted fabric, a nonwoven fabric, paper, or a laminate thereof can be used. Among these, those having elasticity such as a knitted fabric are preferable from the viewpoint that the adhesiveness of the patch to the skin is more easily secured, and those having self-supporting properties from the viewpoint of handling properties of the patch. (For example, a film and a sheet-like foam) are preferable. The thickness of such a support layer is preferably 10 to 1500 μm.

The preferred embodiments of the pressure-sensitive adhesive layer and the support layer provided in the patch of the present invention have been described above. However, the patch of the present invention covers the surface of the pressure-sensitive adhesive layer until the patch is used. In order to protect it, a release liner layer may be further provided. The material of the release liner layer is not particularly limited, but it is preferable to use a sheet-like material made of polyester, polypropylene, polyethylene, paper, or a laminate thereof subjected to a release treatment (silicone coating or the like). . The thickness of such a release liner layer is preferably 25 to 150 μm.

Furthermore, the area of the patch of the present invention is usually not particularly limited as long as it can be arbitrarily set in the range of 1 to 1000 cm ² and can achieve a therapeutically effective amount of diclofenac skin permeation. It is preferable that the area is 50 to 200 cm ² from the viewpoint of facilitating adhesion and ensuring sufficient adhesive strength that does not peel off during application.

Further, the patch of the present invention suppresses crystal precipitation of diclofenac and diclofenac sodium, and stably contains diclofenac sodium at a high concentration (3% by mass or more based on the total mass of the pressure-sensitive adhesive layer). it can. Furthermore, since the drug release property (water release property) from the pressure-sensitive adhesive layer is high, a larger amount of diclofenac can be absorbed percutaneously than existing patches. That is, as shown in the examples described later, according to the patch of the present invention, in the human skin permeability test, as a cumulative permeation amount for 24 hours from the start of measurement, a large amount (blood concentration) of 50 μg / cm ² or more. Of diclofenac can be administered into the body.

The patch of the present invention is not particularly limited, and can be produced by appropriately adopting a known method for producing a patch. For example, first, various components other than diclofenac sodium constituting the pressure-sensitive adhesive layer are each heated and mixed in a predetermined ratio under an inert atmosphere such as nitrogen, and then diclofenac sodium is added in a predetermined ratio. Further stirring is performed to obtain a uniform dissolved product. Next, the melted product thus obtained is directly applied on the surface of the support layer (usually on one surface) with a predetermined thickness according to a conventional method to form an adhesive layer. Next, the patch of the present invention can be obtained by covering the surface of the pressure-sensitive adhesive layer opposite to the support layer with a release liner layer and then cutting it into a desired shape. Alternatively, the melt is first applied on one surface of the release liner layer with a predetermined thickness to form an adhesive layer, and then a support layer on the surface of the adhesive layer opposite to the release liner layer. The adhesive patch of the present invention may be obtained by pressure-transferring and cutting into a desired shape.

Further, the above components and diclofenac sodium may be added to an organic solvent such as hexane, toluene, ethyl acetate or the like so as to have a predetermined ratio, and stirred to obtain a uniform dissolved product (adhesive layer composition). . And after apply | coating this melt | dissolution to predetermined | prescribed thickness on one surface of a support body layer and drying with a dryer etc., volatilizing and removing the organic solvent, and forming the adhesive layer, the said adhesive layer's said The patch of the present invention can be obtained by covering the surface opposite to the support layer with a release liner layer and then cutting it into a desired shape. Alternatively, the dissolved material is first applied on one surface of the release liner layer with a predetermined thickness, dried by a drier or the like, the organic solvent is removed by volatilization, and the pressure-sensitive adhesive layer is formed. The patch of the present invention may be obtained by pressure-transferring the support layer on the surface opposite to the release liner layer and cutting it into a desired shape.

Hereinafter, the present invention will be described more specifically based on examples and comparative examples, but the present invention is not limited to the following examples. In the patches obtained in each Example and Comparative Example, evaluation of crystal precipitation, skin irritation test, skin permeation test, water release test, and adhesive strength test were performed by the methods shown below.

(Evaluation of crystal precipitation)
Each patch was stored at 60 ° C. for 2 weeks. Next, the crystal state of diclofenac and diclofenac sodium deposited in a predetermined region on the surface of the adhesive layer of each patch was observed with the naked eye or an optical microscope, and evaluated based on the three-stage index representing the crystal precipitation state below. .
0: No crystal deposition on the pressure-sensitive adhesive surface 1: Sparse crystal deposition is observed on the pressure-sensitive adhesive surface 2: Crystal deposition is observed on almost the entire surface of the pressure-sensitive adhesive.

(Skin irritation test)
A patch obtained by cutting the release liner layer by cutting to a size of 3 cm ² was applied to the skin of the back of six subjects (healthy subjects). Then, it peels off after 24 hours from pasting, and then the change of the skin at the pasting site after 24 hours is visually observed, scored against the following four levels of indices, and the average value of these scores is calculated. The skin irritation of each patch was evaluated.
0: No erythema 1: Very mild erythema 2: Obvious erythema 3: Moderate to strong erythema

(Skin penetration test)
The dorsal skin of the hairless mouse was peeled off and attached to a Franz-type flow-through cell in which hot water of 32 ° C. was circulated to the outer peripheral portion so that the dermis side was the receptor tank side. Then, a patch obtained by cutting the release liner layer by cutting to a size of 3 cm ² was attached to the skin stratum corneum side. A phosphate buffer solution (pH 7.4) is flowed into the receptor tank of the flow-through cell at a flow rate of 5 mL / hr, and a sample solution for 24 hours from the start of measurement is taken every 3 to 4 hours from the receptor tank. The concentration of the drug (diclofenac) was measured for each collected sample solution by a high performance liquid chromatograph (HPLC) method. From the obtained measured value, the amount of drug permeation per hour (F; μg / cm ² / hr) was calculated by the following formula:
F (μg / cm ² / hr) = [drug concentration (μg / ml) × flow rate (ml)] / patch area (cm ² ) / hour (hr)
The cumulative amount of drug permeation through the skin (μg / cm ² ) was determined by integrating the obtained amount of drug permeation. A patch having a large cumulative skin permeation value is recognized as having excellent drug skin permeability.

Further, a patch obtained by cutting to a size of 3 cm ² and removing the release liner layer was attached to the stratum corneum side of the human cadaver excised skin dermatomed to 500 μm. Then, as in the permeation test using the back skin of the hairless mouse, the cumulative drug permeation amount in each patch on human skin was determined.

(Water release test)
The test was conducted under the following conditions in accordance with a water release test using a rotating cylinder described in the US Pharmacopoeia Release Test Method. That is, the patch from which the release liner layer was removed by cutting to a size of 3 cm ² was fixed to the cylinder with the adhesive on the support layer side, and test solution: phosphate buffer solution (PBS) having a pH of 7.4, The test was carried out under the conditions of liquid temperature: 32 ° C., distance between lower end of cylinder and inner surface of bottom of container: 25 mm, rotation speed: 50 rpm. And the test liquid was extract | collected 0 hours, 1 hour, 3 hours, 6 hours, and 24 hours after the test start, the quantity of the diclofenac released by HPLC method was quantified, and the discharge | release amount with respect to the theoretical content was calculated | required in%.

(Adhesion test (peel test))
A patch that has been cut to a size of 1 cm × 4 cm to remove the release liner layer is applied to a cleaned bakelite test plate with the adhesive layer of the patch on the bottom, And then crimped with a roller. About 30 minutes after crimping, set on an Instron type tensile tester (trade name: Tensilon, manufactured by A & D) and measure the force (gf) required for 180 ° peeling at 300 mm / min. did.

(Comparative Examples 1 and 2)
First, the components described in Table 1 were weighed so as to have a predetermined mass%, and further toluene was added and mixed to dissolve or disperse, thereby obtaining an adhesive layer composition. Next, by coating on one side of the release paper (silicone-treated PET film), after drying, cover the surface opposite to the release paper with a support layer (PET film), and press-bond, A patch was obtained. And about the obtained patch, the result of having evaluated the crystal precipitation of diclofenac and diclofenac sodium is shown in Table 1 with the composition of an adhesive layer composition. The numerical values in parentheses in Table 1 indicate the respective components (dimethyl sulfoxide, N-methyl-2-pyrrolidone or dipropylene glycol) when 1 part by mass of diclofenac sodium in the adhesive layer composition of each comparative example is used. The mass part is shown.

As is clear from the results shown in Table 1, when only diclofenac sodium and citric acid were added, diclofenac or diclofenac sodium crystallized over time in the adhesive layer of the patch. Therefore, in order to search for a component that suppresses the precipitation of diclofenac and diclofenac sodium crystals over time and contains diclofenac sodium at a high concentration (more than 3% by mass) in the adhesive layer, diclofenac and The solubility of diclofenac sodium was measured. The obtained results are shown in FIGS.

As is apparent from the results shown in FIG. 1, diclofenac is a dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), polyethylene glycol (PEG-400), dipropylene glycol (DPG) having a high concentration of 100 mg / ml or more. Dissolved in concentration.

In addition, as is apparent from the results shown in FIG. 2, diclofenac sodium was also added to dimethyl sulfoxide, dipropylene glycol, N-methylpyrrolidone, and polyethylene glycol at a high concentration of 100 mg / ml or more in the same manner as diclofenac, which is its free form. Dissolved.

However, although not shown in the figure, when dimethyl sulfoxide is blended in the adhesive layer, the solubility of diclofenac sodium in the initial stage of production is good, but crystals form over time, and as with citric acid, only dimethyl sulfoxide is present. Then, it became clear that it was unsuitable for use as a solubilizing agent for diclofenac sodium in patches.

(Examples 1 to 4, Comparative Examples 3 and 4)
First, the components described in Table 2 were weighed so as to have a predetermined mass%, and further toluene was added and mixed to dissolve or disperse, thereby obtaining an adhesive layer composition. Next, as in Comparative Examples 1 and 2, a patch was obtained by coating on one surface of the release paper, drying, covering the surface opposite to the release paper with a support layer, and press-bonding. It was. And about the obtained patch, the result of having evaluated the crystal precipitation of diclofenac and diclofenac sodium is shown in Table 2 with the composition of an adhesive layer composition. Moreover, the numerical value in the bracket | parenthesis of Table 2 shows the mass part of each component (dimethyl sulfoxide or a citric acid) when the diclofenac sodium in the adhesive layer composition of each Example and a comparative example is 1 mass part. Yes.

As is apparent from the results shown in Table 2, the patch of the present invention, that is, the pressure-sensitive adhesive layer contains diclofenac sodium, dimethyl sulfoxide and citric acid, and the mass ratio of diclofenac sodium and citric acid. Is 1: 0.15 to 1: 0.45, and the mass ratio of diclofenac sodium to dimethyl sulfoxide (the mass of diclofenac sodium: the mass of dimethyl sulfoxide) is 1: 0.75 to 1: 3 In the patches (Examples 1 to 4), crystal precipitation of diclofenac and diclofenac sodium was suppressed. On the other hand, in the patch (Comparative Examples 3 and 4) not provided with the pressure-sensitive adhesive layer according to the present invention, crystals of diclofenac or diclofenac sodium were deposited over time.

(Comparative Examples 5 to 8)
First, the components described in Table 3 were weighed so as to have a predetermined mass%, and further toluene was added and mixed to dissolve or disperse to obtain an adhesive layer composition. Next, as in Comparative Examples 1 and 2, a patch was obtained by coating on one surface of the release paper, drying, covering the surface opposite to the release paper with a support layer, and press-bonding. It was. And about the obtained patch, the result of having evaluated skin irritation is shown in Table 3 with the composition of an adhesive layer composition. The numerical values in parentheses in Table 3 indicate the respective components (dimethyl sulfoxide, N-methyl-2-pyrrolidone, dithiophene) when 1 part by mass of diclofenac sodium in the adhesive layer composition of each example and comparative example is used. Part by weight of propylene glycol or citric acid).

As is apparent from the results shown in Table 3, the patch of the present invention, that is, the pressure-sensitive adhesive layer contains diclofenac sodium, dimethyl sulfoxide and citric acid, and the mass of diclofenac sodium and citric acid. The mass ratio of the diclofenac sodium to the dimethyl sulfoxide (the mass of diclofenac sodium: the mass of dimethyl sulfoxide) is 1: 0.75 to 1: 3. In some patches (Examples 2 and 3), no skin irritation was observed. On the other hand, in a patch (Comparative Examples 6 and 7) having a pressure-sensitive adhesive layer containing dimethyl sulfoxide in the pressure-sensitive adhesive layer and containing mesylic acid or ammonium chloride instead of citric acid, strong skin irritation is present. Admitted.

Moreover, the skin permeability of diclofenac sodium in mouse skin was evaluated for the patch of Example 2 and the commercially available 1% diclofenac sodium-containing patch (Comparative Example 12). The obtained results are shown in FIG. Moreover, about the patch of Example 2 and Comparative Example 12, the skin permeability of diclofenac sodium in human skin was evaluated. The obtained results are shown in FIG.

As is apparent from the results shown in FIGS. 3 and 4, the patch of the present invention for both mouse and human skin is compared with the patch that does not include the adhesive layer according to the present invention. A large amount of diclofenac per unit area could be permeated.

Next, based on the results of the human skin permeability evaluation shown in FIG. 4, the pharmacokinetics in humans in the case where 1 to 3 patches (area: 140 cm ² ) of Example 2 were applied to the skin were described above. Convolution was performed and predicted based on the results of a skin penetration test. Also, diclofenac sodium-containing oral preparations (Voltaren (registered trademark) tablets (content 25 mg, taken three times a day) and Voltaren (registered trademark) SR capsules (content 37.5 mg, taken twice a day)) are also attached. Predictions were based on documented pharmacokinetic data. The obtained results are shown in FIGS.

As is apparent from the results shown in FIGS. 5 to 7, when 2 to 3 patches (Example 2, area: 140 cm ² ) of the present invention are applied, the area under the blood concentration almost equal to that of the oral preparation is applied. (AUC) could be obtained.

(Examples 5 to 9 and Comparative Examples 9 to 11)
First, the components described in Table 4 were weighed so as to have a predetermined mass%, and further toluene was added and mixed to dissolve or disperse, thereby obtaining an adhesive layer composition. Next, as in Comparative Examples 1 and 2, a patch was obtained by coating on one surface of the release paper, drying, covering the surface opposite to the release paper with a support layer, and press-bonding. It was. In addition, the numerical value in the bracket | parenthesis of Table 4 is a mass part of each component (Dimethylsulfoxide, a citric acid, or ammonium chloride) when the diclofenac sodium in the adhesive layer composition of each Example and a comparative example is 1 mass part. Is shown.

Then, water release properties of the patches of Examples 5 to 9 and Comparative Examples 10 and 11 were evaluated, and the obtained results are shown in FIG. As is apparent from the results shown in FIG. 8, the patch of the present invention, that is, the pressure-sensitive adhesive layer contains diclofenac sodium, dimethyl sulfoxide and citric acid, and the mass of diclofenac sodium and citric acid. The mass ratio of the diclofenac sodium to the dimethyl sulfoxide (the mass of diclofenac sodium: the mass of dimethyl sulfoxide) is 1: 0.75 to 1: 3. Certain patches (Examples 5 to 9) are superior in terms of water release (drug release) as compared to patches (Comparative Examples 10 and 11) that do not have the adhesive layer according to the present invention. It was.

Further, the adhesive strength of the patches of Examples 5 to 9 and Comparative Examples 10 and 11 was evaluated. The results obtained are shown in Table 5. The amounts of citric acid and dimethyl sulfoxide (DMSO) listed in Table 5 indicate the parts by mass of each component when the amount of diclofenac sodium in the adhesive layer composition of each example and comparative example is 1 part by mass. ing.

As apparent from the results shown in Table 5, the pressure-sensitive adhesive layer contains diclofenac sodium, dimethyl sulfoxide and citric acid, and the mass ratio of diclofenac sodium to dimethyl sulfoxide (mass of diclofenac sodium: dimethyl sulfoxide). The patches (Examples 5 to 8 and Comparative Examples 10 and 11) each having a pressure-sensitive adhesive layer having a mass ratio of 1: 0.2 to 1: 2 had strong adhesive strength. On the other hand, a patch (Example 9) having an adhesive layer containing 3 parts by mass of the dimethyl sulfoxide, that is, more than 2 parts by mass with respect to 1 part by mass of the diclofenac sodium, is not satisfactory in terms of adhesive strength. It was enough.

As described above, according to the present invention, it is possible to provide a patch that suppresses crystal precipitation of diclofenac and diclofenac sodium, has less irritation to the skin, and is excellent in skin permeability of diclofenac. .

Therefore, the patch of the present invention suppresses crystal precipitation of diclofenac and diclofenac sodium, and stably contains diclofenac sodium at a high concentration (3% by mass or more based on the total mass of the pressure-sensitive adhesive layer). In addition, since it can exhibit excellent skin permeability of diclofenac, it is useful not only as a drug for local analgesia and anti-inflammatory but also as a drug for systemic analgesia and anti-inflammation.

Claims

A patch comprising a support layer and an adhesive layer,
The pressure-sensitive adhesive layer contains diclofenac sodium, dimethyl sulfoxide, and citric acid, and the mass ratio of diclofenac sodium to citric acid (mass of diclofenac sodium: mass of citric acid) is 1: 0.15 to 1 A patch having a mass ratio of 0.45 to diclofenac sodium and dimethyl sulfoxide (diclofenac sodium mass: dimethyl sulfoxide mass) of 1: 0.75 to 1: 3.
The patch according to claim 1, wherein the mass ratio of the diclofenac sodium and the dimethyl sulfoxide is 1: 1 to 1: 2.
The patch according to claim 1 or 2, wherein the pressure-sensitive adhesive layer further contains oleic acid.